This is a multi-center, prospective active surveillance study with selective intervention in patients with previously untreated, clinically localized prostate cancer at diagnosis. Candidates are assessed based on an extended core biopsy, serum PSA (including PSA kinetics, if available), digital rectal examination (DRE), and assessment of cancer grade and extent.
Active surveillance is defined as serial PSA measurements and prostate examination with routine prostate biopsy and therapeutic intervention considered at the time of one or more of the following:
Grade or volume progression
This protocol is not designed as a formal clinical trial with randomization of different treatments, although the following measures will be obtained:
Blood, urine and tissue specimen banking for biomarker studies
Rates of radical intervention
Discover and confirm biomarkers that predict aggressive disease as defined by pre-specified histological, PSA, clinical criteria, or outcomes based on these variables.
The primary objective of this repository is to discover and validate biomarkers predicting aggressive disease, with emphasis on validation. The sample size and power is based on validation of a biomarker after its initial discovery. Since this cohort of men has already elected AS, a desirable biomarker should have high specificity so that clinicians will minimize the proportion of those men advised for more aggressive treatment, while still identifying the subset of men with high risk for progression. Therefore, we evaluate the sensitivity of a biomarker predicting aggressive disease at 95% specificity. We assume the threshold for 95% specificity needs to be estimated from this study, i.e., there is no pre-fixed threshold. This is more realistic because estimating the threshold usually requires a large study. The proportion of disease progression at 3 and 5 years from diagnosis is estimated at 25% and 33%. We want 90% power to confirm a sensitivity better than 10% (unacceptable) if the true sensitivity is 30% or better, at 95% specificity. Point estimate of sensitivity, specificity, and threshold and their 95% confidence intervals will be calculated. The sample size also depends on the slope of Receiver Operating Characteristic (ROC) curve at 95% specificity, usually quite steep when specificity is near 100%. We used 4 as the slope parameter for power analysis.
Based on above assumptions, for a cohort with at least 3 years follow up, this study requires 100 men with disease progression and 300 men without progression, totally n=400. For a cohort with at least 5 years follow up, this study requires 125 men with progression and 250 men without progression, total n=375. Therefore, the total needed person-years follow up should be 375*5=1,875.
The estimated number of patients elected for AS is about 350 in five sites combined. Given a conventional 25% recruitment rate, we expect 100 patients per year accrual. With 25% loss of follow-up, we estimate that each year’s 100 recruited men will finally contribute 375 person-years by the end of 5 years. It should be noted that we need full 5 years follow up to ensure that the men who had not progressed are indeed non-progressors, not false negatives. By the same reason, men after 5-years follow up will contribute little to the total person-years follow up because their risk of progression is felt to be low. Therefore, the study needs continuing 5 years recruitment and subsequent 5-years follow up with minimum 100 recruitment per year and a minimum 75% follow up rate.